Anti-dandruff composition

ABSTRACT

Described herein is an anti-dandruff composition including at least two anti-dandruff actives selected from a punicalagin composition; a first monoterpenoid composition, or a second monoterpenoid composition; and a dermatologically-acceptable carrier. The two or more anti-dandruff actives are present in the anti-dandruff composition in an effective amount to treat or prevent dandruff caused by the proliferation of  Malassezia furfur.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the US national phase under 35 U.S.C. § 371 ofInternational Application No. PCT/IB2019/000370, filed May 16, 2019,which claims priority to Indian Patent Application No. 201821018779filed May 18, 2018, the contents of each of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to antimicrobial compositions comprisingnaturally-derived anti-dandruff active materials, and more particularlyto an anti-dandruff composition comprising a combination of apunicalagin composition and select monoterpenoid essential oils, thecombinations of which are effective to inhibit Malassezia furfur andtreat dandruff.

BACKGROUND OF THE INVENTION

Dandruff corresponds to excessive and visible desquamation of the scalpresulting from the excessively rapid multiplication of the epidermalcells and from their abnormal maturation. A variety of factors caninduce this condition, such as excessive hair treatments, extremeclimatic conditions, nervousness, diet, fatigue, or pollution. However,dandruff conditions most commonly arise from a disorder of themicroflora of the scalp and more particularly from the excessivecolonization by a fungus that belongs to the family of the yeasts of thegenus Malassezia, which is naturally present on the scalp.

Dandruff, which affects up to 50% of the world's population and affectsboth men and women, generally has a negative psychosocial impact.Dandruff is disagreeable aesthetically (due to the visible presence ofdead skin flakes) and because of the personal discomfort felt by theindividual (in particular itching). Accordingly, affected personsconfronted with this problem to variable degrees wish to be rid of itefficiently and permanently.

Many anti-dandruff treatments have been developed with the mainobjective of eradicating Malassezia yeasts from the scalp. Thus, theactivity of the anti-dandruff active agents of today, such as zincpyrithione, piroctone olamine, climbazole, ketoconazole, or seleniumdi-sulfide, are based mainly on their fungicidal property. Recently,other formulations using nature-based alternatives have been described,such as an anti-dandruff composition based on ellagic acid and at leastone essential oil as described in WO2011/138450, or a hydrolysabletannin-enriched active substance derived from Punica granatum asdescribed in FR2908045.

Despite the foregoing, there continues to be a need for new effectivenatural solutions toward treating dandruff.

SUMMARY OF THE INVENTION

The present invention is premised on the realization that variouscombinations of anti-dandruff actives, selected from a punicalagincomposition, a first monoterpenoid composition comprising (or consistingessentially of) p-cymene; and a second monoterpenoid compositioncomprising (or consisting essentially of) menthol, are effective toinhibit Malassezia furfur and thereby treat dandruff.

Thus, in accordance with an embodiment of the present invention, ananti-dandruff composition is provided that comprises (or consistsessentially of) a combination of at least two anti-dandruff activesselected from the group consisting of a punicalagin composition; a firstmonoterpenoid composition comprising (or consisting essentially of)p-cymene; and a second monoterpenoid composition comprising (orconsisting essentially of) menthol; and a dermatologically-acceptablecarrier. The anti-dandruff actives are present in the anti-dandruffcomposition in an effective amount to treat or prevent dandruff.

In accordance with another embodiment of the present invention, ananti-dandruff hair care composition is provided that is suitable for thetreatment of dandruff against Malassezia furfur. The compositionincludes the anti-dandruff actives, a dermatologically-acceptablecarrier, and a shampoo matrix comprising at least one detersivesurfactant selected from the group consisting of an anionic surfactant,a nonionic surfactant, an amphoteric surfactant, or a combinationthereof.

In accordance with yet another embodiment of the present invention, amethod for treating dandruff conditions associated with theproliferation of yeasts of the Malassezia genus on a scalp of a subjectis provided. The method comprises applying an effective amount of theanti-dandruff composition to the scalp of the subject, wherein theeffective amount of the anti-dandruff composition inhibits theproliferation of the yeasts of the Malassezia genus on the scalp.

The objects and advantages of the present invention will be furtherappreciated in light of the following detailed description and examples.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention relates to anti-dandruff compositions, and methodsof using those compositions to treat or inhibit dandruff. Theanti-dandruff compositions are useful for application to keratinoustissue or scalp surface and comprise an effective amount of acombination of anti-dandruff actives, and which inhibit, reduce, oreliminate dandruff symptoms arising from the proliferation of Malasseziafurfur. The anti-dandruff compositions may be in a wide variety ofproduct forms that include, but are not limited to, solutions,suspensions, lotions, creams, gels, ointments, sprays, aerosols,shampoos, hair conditioners, pastes, foams, powders, mousses, wipes,strips, patches, hydrogels, film-forming products, and the like. Thecompositional form may follow from the particulardermatologically-acceptable carrier chosen.

As used herein, the term “anti-dandruff composition” includescompositions that are applied to the hair and/or the skin underneath thehair, and comprise (or consist essentially of) at least one of variouscombinations of a punicalagin composition; a first monoterpenoidcomposition comprising (or consisting essentially of) p-cymene; and asecond monoterpenoid composition comprising (or consisting essentiallyof) menthol; and a dermatologically-acceptable carrier, the combinationsof which are effective to inhibit Malassezia furfur and treat dandruff.

The term “topical application,” as used herein, means to apply or spreadthe compositions of the present invention onto the surface of the scalpfrom which mammalian hair grows.

The term “dermatologically-acceptable,” as used herein, means that thecompositions or components thereof so described are suitable for use incontact with mammalian keratinous or skin tissue without undue toxicity,incompatibility, instability, allergic response, and the like.

The term “anti-dandruff active”, as used herein, refers to a singlecompound or a composition that possesses an ability to inhibit theproliferation of Malassezia furfur, when present in a medium in aneffective amount.

The term “effective amount,” as used herein, means an amount of acompound or composition sufficient to reduce or inhibit theproliferation of Malassezia furfur, reduce or inhibit the visibleeffects of dandruff caused by the proliferation of Malassezia furfur, orreduce or inhibit scalp pruritus, by a statistically significant amount.

The term “minimum inhibitory concentration,” also abbreviated as “MIC,”refers to the lowest concentration of the anti-dandruff active that willinhibit the growth of Malassezia furfur after incubation (at least 24hours to 72 hours; 32.5° C.±2.5° C.) of a 1% agar solution mixed with anequal volume of an inoculated broth. Inhibition is defined as givingless than 20% growth compared to a control, as determined byspectrophotometric optical density (OD) reading at 620 nm, using theformula % ofgrowth=[(OD_(product)−OC_(absorbance-control))]/(OD_(positive growth-control)).

Anti-Dandruff Composition

In accordance with embodiments of the present invention, theanti-dandruff composition comprises (or consists essentially of) aneffective amount of a combination of at least two anti-dandruff activesselected from the group consisting of A) a punicalagin composition; B) afirst monoterpenoid composition comprising (or consisting essentiallyof) p-cymene; and C) a second monoterpenoid composition comprising (orconsisting essentially of) menthol; the combination of which iseffective to inhibit Malassezia furfur and treat dandruff; and adermatologically-acceptable carrier.

A. Punicalagin Composition

The term “punicalagin composition,” as used herein, refers to acomposition comprising at least 0.1 weight percent (wt %) of punicalaginA, punicalagin B, or a combination of the anomers. For example, thepunicalagin content of the punicalagin composition may be, on a dryweight basis, 0.2 wt %, 1 wt %, 5 wt %, 10 wt %, 20 wt %, 30 wt %, 50 wt%, 75 wt %, or more, or within a range between any two of the foregoing.In one embodiment, the punicalagin content of the punicalagincomposition is, on a dry weight basis, 30 wt % or more. Punicalagin maybe synthetic or may be derived from a botanical such as Punica granatum(pomegranate), Terminalia catappa (Indian-almond), Terminalia myriocarpa(East Indian almond), or Combretum molle (velvet bushwillow). Inaccordance with an embodiment, the punicalagin composition is derivedfrom Punica granatum. For example, the punicalagin composition may be apomegranate extract.

The term “pomegranate extract,” as used herein, refers to a productobtained by an extractive process from pomegranate (Punica granatum).Pomegranates are rich in antioxidants, with that activity beingprimarily attributable to polyphenols such as punicalagin A and B,punicalin, ellagic acid, gallic acid, etc. and often expressed in termsof gallic acid equivalents (GAE). While also present in pomegranatebark, seed, pulp, juice, and pericarp, the majority of the punicalaginsand other ellagitannins, such as punicalin, is found in the skin (alsocalled the rind or peel) of the fruit. Thus, in accordance with anembodiment, the solid pomegranate material may be a dried pomegranaterind or peel, which has been ground or flaked to reduce particle sizethereby increasing the available surface area for extraction. In anotherembodiment, fresh pomegranate peels are utilized.

Accordingly, in one embodiment, the pomegranate extract is a compositionproduced by a general method comprising the steps of: (a) contacting asolid pomegranate material with an aqueous extraction liquid (e.g.,water or a mixture of a water-miscible organic solvent and water); and(b) filtering or centrifuging the resulting mixture to separate theextracted pomegranate solids from the aqueous fraction. The process maybe repeated multiple times, and the combined aqueous fractionsconcentrated to remove the water-miscible organic solvent, water, and/orany other volatiles. The pomegranate extract can be standardized bydilution to a desired extent with an appropriate diluent.

The selection of a suitable water-miscible organic solvent for theaqueous extraction liquid is not particularly limited, so long as thedesired punicalagins are soluble therein. Non-limiting examples includemethanol, ethanol, propanol, butanol, acetone, propylene glycol,butylene glycol, dimethylformamide, dimethyl sulfoxide, or combinationsthereof. The volume ratio between the water-miscible organic solvent andwater can vary between about 9:1 to about 1:9, for example about 7:1,about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:7, or ina range between any two of the foregoing. In an embodiment, the aqueousextraction liquid is water. In another embodiment, the aqueousextraction liquid is an aqueous alcoholic solution. For example, theaqueous extraction liquid may be water, or it may comprise a 1:1 mixtureof ethanol and water (i.e., 50% aqueous ethanol).

The ratio of the mass of the extracting solution to the mass ofpomegranate solids can vary depending on a variety of factors, such asvessel size, extraction efficiency, and the like. A suitable range ofratios includes, but is not limited to, about 1:1 to about 25:1, such as2:1, 4:1, 6:1, 8:1, 10:1, 15:1, 20:1, or in a range between any two ofthe foregoing.

The pomegranate extraction may be performed at a variety of pressures ortemperatures. For example, the extraction can be conducted at ambientpressure and/or room temperature, or the extraction may be performedunder pressure and/or at an elevated temperature. In one embodiment, thepomegranate extraction is performed near atmospheric pressure, and at atemperature within in a range from about 40° C. to about 100° C., suchas about 50° C., about 60° C., about 70° C., about 80° C., or in a rangebetween any two of the foregoing.

Evaporation (e.g., lyophilization) of the extracting liquids provides asolid, pomegranate extract that is enriched in punicalagin. Inaccordance with an embodiment, the punicalagin composition comprises atleast 0.1 wt % of the punicalagin anomers, on a dry weight basis of theextract. In accordance with another embodiment, the punicalagincomposition comprises less than 5 wt % of ellagic acid, on a dry weightbasis of the extract. In accordance with another embodiment, thepunicalagin composition comprises a polyphenol content of at least 30GAE (by Folin—Ciocalteu Method), on a dry weight basis of the extract.If desired, the punicalagin composition may be standardized to a targetpolyphenol content with an acceptable diluent. A non-limiting example ofa suitable diluent is a polyol, such as glycerol. In one example, thepunicalagin composition is diluted with glycerol to provide astandardized solution having a phenolic content of 12% GAE.

In accordance with another embodiment, the pomegranate extract may beprocessed to further enrich the punicalagin concentration. For example,the pomegranate extract may be purified using chromatographic,precipitation, complexation, or other standard techniques to increasethe punicalagin content of the extract. For example, the punicalagincontent of the pomegranate extract may be, on a dry weight basis, 0.2 wt%, 1 wt %, 5 wt %, 10 wt %, 20 wt %, 30 wt %, 50 wt %, 75 wt %, or more,or within a range between any two of the foregoing. In one embodiment,the punicalagin content of the punicalagin composition is 30 wt % ormore, on a dry weight basis of the extract.

In one example, extraction of dried, flaked pomegranate rind (having apolyphenolic content of about 20-25 wt % as determined byFolin-Ciocalteu Method) is performed six times with 50% aqueous ethanol(liquid to solid mass ratio of about 4:1) at 60° C. to 70° C. Thecombined liquids were filtered, and then evaporated to near dryness toprovide a solid material having a phenolic content of approximately40-45% GAE. Analysis of the crude extract using High Performance LiquidChromatography—Quadrupole Time of Flight Liquid (HPLC-QTOF) confirmedthe presence of gallic acid, punicalagins A and B, punicalin, ellagicacid hexoside, ellagic acid pentoside, ellagic acid deoxyhexoside,ellagic acid, and galloyl HHDP hexoside. Quantification by HPLC revealedthat ellagic acid was present in less than 5 wt %. The ellagic acidcontent may be further reduced using standard techniques, such asselective solvent treatments or column chromatography, to a level of 1wt % or less, based on total weight of the punicalagin composition,where weight percentage is on a dry weight basis.

In vitro Inhibition testing of the pomegranate extract againstMalassezia furfur, in accordance with the classic broth dilutionprotocol, revealed that the pomegranate extract possessed a minimuminhibition concentration (MIC) value of ≤0.1% against Malassezia furfurCIP 1634.84. Inhibition testing on a substantially pure sample of thepunicalagin anomers (A:B, 1:2; 93 wt % pure; part No. 00016983,Chromadex, Inc., Irvice, CA), yielded a MIC value of 0.05% againstMalassezia furfur CBS 1878. In comparison, ellagic acid (>95 wt %, prod.No. E2250, Sigma-Aldrich, St. Louis, MO) demonstrated a MIC value of0.5% against Malassezia furfur CBS 1878.

In another embodiment, fresh peels are separated from the arils of wholepomegranates, and the peels, which may be subjected to size reduction,are mixed with water. The aqueous portions are collected and the solidresidue pressed to expel residual aqueous fluid. This process may berepeated three or more times. The combined aqueous portions arecentrifuged to remove suspended solids, and the aqueous portions passedthrough a packed column containing DIAION™ HP20 resin (MitsubishiChemical, Japan) to adsorb the polyphenols. Elution with 50% aqueousethanol provided fractions rich in punicalagins, which were concentratedand spray dried to provide a solid pomegranate extract with a phenoliccontent of 70-75% GAE, with approximately 30 wt % punicalagins. Astandardized solution was prepared by dilution with glycerol to aphenolic content of 12% GAE. In vitro inhibition testing of thisstandardized solution against Malassezia furfur CBS 1878, in accordancewith the classic broth dilution protocol, revealed a minimum inhibitionconcentration (MIC) value of ≤0.05%. Thus, it was observed thatincreasing the punicalagin content of the pomegranate extract furtherreduces its MIC value against Malassezia furfur.

B. First Monoterpenoid Composition

The term “first monoterpenoid composition,” as used herein, refers to acomposition comprising (or consisting essentially of) para-cymene. In anembodiment, the first monoterpenoid composition comprises (or consistsessentially of) para-cymene and thymol. In another embodiment, the firstmonoterpenoid composition further comprises (or consists essentially of)para-cymene and gamma-terpinene. In yet another embodiment, the firstmonoterpenoid composition comprises (or consists essentially of)para-cymene, thymol, and gamma-terpinene. In an embodiment, thepara-cymene content of the first monoterpenoid composition is at least20 wt %.

In an embodiment, the first monoterpenoid composition comprises 20-60 wt% gamma-terpinene, 20-60 wt % para-cymene, and 20-60 wt % thymol. Inanother embodiment, the combined masses of the gamma-terpinene,para-cymene, and thymol constitute at least 80 wt % of the firstmonoterpenoid composition. In yet another embodiment, the firstmonoterpenoid composition comprises gamma-terpinene, para-cymene, andthymol in a mass ratio of about 2:1:1, respectively.

In another embodiment, the first monoterpenoid composition is derivedfrom an ajowan (Trachyspermum ammi syn Carum copticum) essential oil. Asused herein, the term “essential oil,” refers to a concentratedhydrophobic liquid containing volatile aroma compounds from a botanical(plant) source, which may include the plant roots, leaves, stems,fruits, seeds, rinds, etc. Generally speaking, selection of thetechnique for obtaining an essential oil depends mainly on the startingmaterial, i.e., the plant's original state, its characteristics, and thenature of its aroma compounds. The technique conditions thecharacteristics of the essential oil, in particular viscosity, color,solubility, volatility, and richness or poorness in certainconstituents. Common techniques for obtaining essential oils includesolvent or supercritical fluid extractions, cold pressing, ordistillation, which can be carried out under a variety of conditions,e.g., dry distillation, hydrodistillation, steam distillation, etc.

In accordance with an embodiment, the ajowan essential oil is obtainedby steam distillation. Generally, steam distillation corresponds to thevaporization, in the presence of steam, of a substance that is not verymiscible with water. The starting material together with water broughtto boiling point (hydrodistillation), or with steam in a still (drydistillation). The steam entrains the essential oil vapor, which iscondensed and recovered as a separate liquid phase from the water.

In an embodiment, the ajowan essential oil is obtained by a typicalsteam distillation process. Ajowan seeds are ground and charged in anextraction vessel. The ground ajowan seeds are moistened first beforeapplying direct steam. A typical steam distillation of ground ajowanseeds takes 10 hours or more until the desired recovery oil content isreached, and provides an oil yield of approximately 2 to 2.5 wt %, basedon the weight of the ground seed starting material. Based on GC/MSanalysis, the ajowan seed steam distilled essential oil includes thefollowing listing of major components gamma-terpinene, thymol, andpara-cymene.

In vitro Inhibition testing of the ajowan essential oil againstMalassezia furfur, in accordance with the classic broth dilutionprotocol, revealed that the ajowan essential oil possessed a minimuminhibition concentration (MIC) value of 0.5% and 1.0% against Malasseziafurfur CIP 1634.84 and Malassezia furfur CBS 1878, respectively. Invitro inhibition testing of the major components of ajowan essential oil(i.e., gamma-terpinene, para-cymene, and thymol) revealed thatgamma-terpinene, para-cymene, and thymol possessed MIC values of >1%,0.5%, and 0.05%, respectively, against Malassezia furfur CBS 1878.

C. Second Monoterpenoid Composition

The term “second monoterpenoid composition,” as used herein, refers to acomposition comprising (or consisting essentially of) menthol. In anembodiment, the second monoterpenoid composition comprises (or consistsessentially of) menthol, menthone, isomenthone, menthyl acetate,neomenthol, limonene, or combinations thereof (e.g. comprises—orconsists essentially of—menthol, menthone, isomenthone, menthyl acetate,neomenthol and limonene). In another embodiment, the secondmonoterpenoid composition comprises 70-80 wt % menthol, 5-10 wt %menthone, 5-10 wt % isomenthone, 5-10 wt % menthyl acetate, 5-10 wt %neomenthol, and 1-5 wt % limonene. In yet another embodiment, the secondmonoterpenoid composition is derived from a corn mint (Mentha arvensis)essential oil. In a typical steam distillation of corn mint to producean essential oil, semi-dried Mentha arvensis is charged to a steamdistillation vessel, packed well, and steam slowly applied to distillout the oil. Depending on a variety of factors, a typical steamdistillation process of corn mint may take between 5 and 7 hours, andprovides an oil yield of approximately 1.4 to 1.6 wt %, based on theweight of the semi-dried corn mint starting material. Based on GC/MSanalysis, the corn mint essential oil product includes the followinglisting of components menthol, menthone, isomenthone, menthyl acetate,neomenthol, and limonene.

In vitro Inhibition testing of the corn mint essential oil againstMalassezia furfur, in accordance with the classic broth dilutionprotocol, revealed that the corn mint essential oil possessed a minimuminhibition concentration (MIC) value of 0.5% against Malassezia furfurCIP 1634.84, and a MIC value of 1% against Malassezia furfur CBS 1878.

As noted above, the anti-dandruff active portion of the anti-dandruffcomposition comprises (or consists essentially of) a combination of atleast two of the three described anti-dandruff actives (i.e., thepunicalagin composition, the first monoterpenoid composition, and thesecond monoterpenoid composition). The combinations are based on theadditive or synergistic relationship between the individualanti-dandruff actives. Inhibition testing of the individualanti-dandruff actives to determine MIC levels followed the principlesand general methods disclosed in C. Lens-Lisbonne, et al. “Methods forthe evaluation of antibacterial activity of essential oils: applicationsto essences of thyme and cinnamon,” J. Pharm. Belg., 1987, 42(5):297-302; and C. Lisbonne “Evaluation of bacteriostatic activity ofessential oils and their components,” Doctoral Thesis, Pharmacy Faculty,Marseille, F R 1988. Interactions of bi-component mixtures (FractionalInhibitory Concentration) were evaluated in accordance with the methoddescribed by J. L. Pons et al., “Evaluation of antimicrobialinteractions between chlorhexidine, quaternary ammonium compounds,preservatives and excipients,” J. Appl. Bacteriol., 1992, 73, 395-400,to assess their additive or synergistic effects.

In an embodiment, the punicalagin-containing pomegranate extract, theajowan essential oil, and the corn mint essential oil, proved to inhibitMalassezia furfur in in vitro experiments at MIC values in a range fromabout 0.1% (w/v) to about 1.0% (w/v). Bi-component mixtures of thepomegranate extract (punicalagins content about 0.2 wt % on a dry weightbasis) and the ajowan essential oil; and the ajowan essential oil andthe corn mint essential oil demonstrated synergistic activities againstMalassezia furfur, whereas the bi-component mixture of the pomegranateextract (punicalagins content about 0.2 wt % on a dry weight basis) andthe corn mint essential oil demonstrated an additive relationship.However, the bi-component mixture of a pomegranate extract having apunicalagins content of about 30 wt % on a dry weight basis and the cornmint essential oil demonstrated synergistic activities againstMalassezia furfur. Additional synergy testing of bi-component mixturesof the pomegranate extract having a punicalagins content of about 30 wt% on a dry weight basis with the major components of the ajowanessential oil (para-cymene, gamma-terpinene, and thymol) revealed thatpunicalagins and para-cymene demonstrated synergistic activities againstMalassezia furfur.

Thus in accordance with an embodiment, the anti-dandruff compositioncomprises (or consists essentially of) a combination of the punicalagincomposition and the second monoterpenoid composition, along with adermatologically-acceptable carrier. In accordance with anotherembodiment, the anti-dandruff composition comprises (or consistsessentially of) a combination of the punicalagin composition and thefirst monoterpenoid composition, along with adermatologically-acceptable carrier. In accordance with yet anotherembodiment, the anti-dandruff composition comprises (or consistsessentially of) a combination of the first and second monoterpenoidcompositions, along with a dermatologically-acceptable carrier. And inaccordance with yet another embodiment, the anti-dandruff compositioncomprises (or consists essentially of) a combination of the punicalagincomposition, the first monoterpenoid composition, and the secondmonoterpenoid composition, along with a dermatologically-acceptablecarrier.

When used as one of the active components, the punicalagin compositionis present in the anti-dandruff composition in an amount between about0.1 wt % and 10 wt %. For example, the punicalagin composition (e.g.pomegranate extract) may comprise 0.1 wt %, 0.2 wt %, 0.5 wt %, 0.75 wt%, 1.0 wt %, 2.0 wt %, 5.0 wt %, 7.5 wt %, 10 wt % of the anti-dandruffcomposition, or in a range between any two of the foregoing. When usedas one of the active components, the first monoterpenoid composition ispresent in the anti-dandruff composition in an amount between about 0.1wt % and 5 wt %. For example, the first monoterpenoid composition (e.g.ajowan essential oil) may comprise 0.1 wt %, 0.2 wt %, 0.5 wt %, 0.75 wt%, 1.0 wt %, 2.0 wt %, 5.0 wt % of the anti-dandruff composition, or ina range between any two of the foregoing. When used as one of the activecomponents, the second monoterpenoid composition is present in theanti-dandruff composition in an amount between about 0.1 wt % and 10 wt%. For example, the second monoterpenoid composition (e.g. corn mintessential oil) may comprise 0.1 wt %, 0.2 wt %, 0.5 wt %, 0.75 wt %, 1.0wt %, 2.0 wt %, 5.0 wt %, 7.5 wt %, 10 wt % of the anti-dandruffcomposition, or in a range between any two of the foregoing. Wt % isbased on the weight of the entire anti-dandruff composition.

D. Dermatologically Acceptable Carrier

The anti-dandruff compositions of the present invention comprise adermatologically-acceptable carrier (which may be referred to as“carrier”) for the anti-dandruff actives composition. A suitable carrieris selected to yield a desired product form. Furthermore, the solubilityor dispersibility of the components may dictate the form and characterof the carrier. In one embodiment, the carrier is present at a level offrom about 30 wt % to about 99 wt %, about 40 wt % to about 98 wt %,about 50 wt % to about 96 wt %, or, alternatively, from about 60 wt % toabout 95 wt %, by weight of the composition. Wt % is based on the weightof the entire composition.

The carrier can be in a wide variety of forms. Non-limiting examplesinclude simple solutions (e.g., aqueous, organic solvent, or oil based),emulsions, and solid forms (e.g., gels, sticks, flowable solids, oramorphous materials). In certain embodiments, the carrier is an aqueouscarrier, which may comprise water or natural botanical juices, such asaloe vera water. In certain embodiments, the dermatologically acceptablecarrier is in the form of an emulsion. Emulsion may be generallyclassified as having a continuous aqueous phase (e.g., oil-in-water andwater-in-oil-in-water) or a continuous oil phase (e.g., water-in-oil andoil-in-water-in-oil). The oil phase of the present invention maycomprise silicone oils, non-silicone oils such as hydrocarbon oils,esters, ethers, and the like, and mixtures thereof.

For emulsions, the aqueous phase comprises water, such as demineralizedor distilled water, for example. Other acceptable carriers that may beused in the aqueous carrier include, but are not limited to alcohol orether compounds, such as ethanol, glycerol, dipropylene glycol,propylene glycol, butylene glycol, 1,4-butanediol,3-allyloxy-1,2-propanediol, dipropylene glycol n-butyl ether,1,2-hexanediol, dimethyl isosorbide, 1,3-propanediol,2,2′-thiodiethanol, and 1,6-hexanediol, or combinations thereof.

The anti-dandruff compositions may have a pH ranging from about 3.0 toabout 10.5, which may be measured by taking a direct pH measurementusing a standard hydrogen electrode of the composition at 25° C.Accordingly, the pH of the anti-dandruff composition may be within therange from about 6 to about 9, for example.

E. Optional Ingredients

The anti-dandruff compositions of the present invention may be preparedin typical anti-dandruff formulations. They may be in the form ofsolutions, dispersion, emulsions, powders, talcs, encapsulated, spheres,spongers, solid dosage forms, foams, and other delivery mechanisms. Thecompositions of the embodiments of the present invention may be hairtonics, leave-on hair products such as conditioners, treatment, andstyling products, rinse-off hair products such as conditioners,shampoos, and treatment products; and any other form that may be appliedto the scalp.

Accordingly, the anti-dandruff compositions may also include othercommon hair ingredients. The CTFA Cosmetic Ingredient Handbook, TenthEdition (published by the Cosmetic, Toiletry, and Fragrance Association,Inc. (now called The Personal Care Products Council), Washington, D.C.)(2004), describes a wide variety of nonlimiting materials that can beadded to the composition herein. Examples of these ingredient classesinclude, but are not limited to: abrasives, absorbents, fragrances,pigments, colorings/colorants, essential oils, skin sensates,astringents, anti-acne agents, anti-caking agents, antifoaming agents,antimicrobial agents, antioxidants, binders, biological additives,buffering agents, bulking agents, chelating agents, film formers,opacifying agents, pH adjusters, propellants, reducing agents,sequestrants, rheology modifiers, conditioning agents, emulsifiers, andsurfactants

In accordance with an embodiment, the anti-dandruff composition may beformulated as a hair care composition, such as a shampoo, a hairconditioner, or a shampoo-conditioner combination, which further includeone or more of the following ingredients 1) surfactants (anionic,amphoteric/zwitterionic, non-ionic), 2) conditioning agents, 3)emulsifiers, 4) opacifiers, 5) thickeners, and 6) buffers. Accordingly,in one embodiment, the anti-dandruff composition of the invention may beformulated as an anti-dandruff hair care composition, with a shampoomatrix comprising at least one detersive surfactant selected from thegroup consisting of an anionic surfactant, a nonionic surfactant, anamphoteric surfactant, or a combination thereof.

1. Surfactants

The hair care composition of the present invention may include adetersive surfactant, which provides cleaning performance to thecomposition. The detersive surfactant in turn may comprise an anionicsurfactant, an amphoteric/zwitterionic surfactant, a non-ionic, ormixtures thereof. Various examples and descriptions of detersivesurfactants are set forth in U.S. Pat. No. 6,649,155; U.S. PatentApplication Publication No. 2008/0317698; and U.S. Patent ApplicationPublication No. 2008/0206355, which are incorporated herein by referencein their entirety.

The concentration of the detersive surfactant component in the hair carecomposition should be sufficient to provide the desired cleaning andlather performance, and generally ranges from about 2 wt % to about 50wt %, from about 5 wt % to about 40 wt %, from about 8 wt % to about 35wt %, or from about 10 wt % to about 30 wt %. Accordingly, the hair carecomposition may comprise a detersive surfactant in an amount of about 5wt %, about 10 wt %, about 12 wt %, about 15 wt %, about 17 wt %, about18 wt %, about 20 wt %, about 25 wt %, about 30 wt %, or in a rangebetween any two of the foregoing, for example. Wt % is based on theweight of the entire composition.

Anionic surfactants suitable for use in the compositions are the alkyland alkyl ether sulfates. Other suitable anionic surfactants are thewater-soluble salts of organic, sulfuric acid reaction products. Stillother suitable anionic surfactants are the reaction products of fattyacids esterified with isethionic acid and neutralized with sodiumhydroxide. Other similar anionic surfactants are described in U.S. Pat.Nos. 2,486,921; 2,486,922; and 2,396,278, which are incorporated hereinby reference in their entirety.

Exemplary anionic surfactants for use in the hair care compositioninclude ammonium lauryl sulfate, ammonium laureth sulfate, triethylaminelauryl sulfate, triethylamine laureth sulfate, triethanolamine laurylsulfate, triethanolamine laureth sulfate, monoethanolamine laurylsulfate, monoethanolamine laureth sulfate, diethanolamine laurylsulfate, diethanolamine laureth sulfate, lauric monoglyceride sodiumsulfate, sodium lauryl sulfate, sodium laureth sulfate, potassium laurylsulfate, potassium laureth sulfate, sodium lauryl sarcosinate, sodiumlauroyl sarcosinate, lauryl sarcosine, cocoyl sarcosine, ammonium cocoylsulfate, ammonium lauroyl sulfate, sodium cocoyl sulfate, sodium lauroylsulfate, potassium cocoyl sulfate, monoethanolamine cocoyl sulfate,sodium tridecyl benzene sulfonate, sodium dodecyl benzene sulfonate,sodium cocoyl isethionate and combinations thereof. In a furtherembodiment of the present invention, the anionic surfactant is sodiumlauryl sulfate, sodium laureth sulfate, or a combination thereof.

Suitable amphoteric/zwitterionic surfactants for use in the hair carecomposition herein include those which are known for use in hair care orother personal care cleansing. Concentrations of such surfactants rangefrom about 0.5 wt % to about 20 wt %, and from about 1 wt % to about 10wt %. Nonlimiting examples of suitable zwitterionic or amphotericsurfactants are described in U.S. Pat. Nos. 5,104,646 and 5,106,609,which are incorporated herein by reference in their entirety.

Amphoteric detersive surfactants suitable for use in the hair carecomposition include those surfactants broadly described as derivativesof aliphatic secondary and tertiary amines in which the aliphaticradical can be straight or branched chain and wherein one of thealiphatic substituents contains from about 8 to about 18 carbon atoms,and at least one contains an anionic group such as carboxy, sulfonate,sulfate, phosphate, or phosphonate. Zwitterionic detersive surfactantssuitable for use in the hair care composition include those surfactantsbroadly described as derivatives of aliphatic quaternary ammonium,phosphonium, and sulfonium compounds, in which the aliphatic radicalscan be straight or branched chain, and wherein one of the aliphaticsubstituents contains from about 8 to about 18 carbon atoms and onecontains an anionic group such as carboxy, sulfonate, sulfate, phosphateor phosphonate. Exemplary amphoteric and/or zwitterionic detersivesurfactants for use in the present hair care composition includecocoamphoacetate, cocoamphodiacetate, lauroamphoacetate,lauroamphodiacetate, cocamidopropyl betaine, cocamidopropylhydroxysultaine, and mixtures thereof.

Nonionic Surfactants: The shampoo compositions can comprise a nonionicsurfactant. Nonionic surfactants include those compounds produced bycondensation of alkylene oxide groups, hydrophilic in nature, with anorganic hydrophobic compound, which may be aliphatic or alkyl aromaticin nature.

Nonlimiting examples of nonionic surfactants for use in the shampoocompositions include the following: (1) polyethylene oxide condensatesof alkyl phenols, e.g., the condensation products of alkyl phenolshaving an alkyl group containing from about 6 to about 20 carbon atomsin either a straight chain or branched chain configuration, withethylene oxide, the said ethylene oxide being present in amounts equalto from about 10 to about 60 moles of ethylene oxide per mole of alkylphenol; (2) those derived from the condensation of ethylene oxide withthe product resulting from the reaction of propylene oxide and ethylenediamine products; (3) condensation products of aliphatic alcohols havingfrom about 8 to about 18 carbon atoms, in either straight chain orbranched chain configurations, with ethylene oxide, e.g., a coconutalcohol ethylene oxide condensate having from about 10 to about 30 molesof ethylene oxide per mole of coconut alcohol, the coconut alcoholfraction having from about 10 to about 14 carbon atoms; (4) long chaintertiary amine oxides of the formula [R¹R²R³N→O] where R¹ contains analkyl, alkenyl or monohydroxy alkyl radical of from about 8 to about 18carbon atoms, from 0 to about 10 ethylene oxide moieties, and from 0 toabout 1 glyceryl moiety, and R² and R³ contain from about 1 to about 3carbon atoms and from 0 to about 1 hydroxy group, e.g., methyl, ethyl,propyl, hydroxyethyl, or hydroxypropyl radicals; (5) long chain tertiaryphosphine oxides of the formula [RR′R″P→O] where R contains an alkyl,alkenyl or monohydroxyalkyl radical ranging from about 8 to about 18carbon atoms in chain length, from 0 to about 10 ethylene oxide moietiesand from 0 to 1 glyceryl moieties and R′ and R″ are each alkyl ormonohydroxyalkyl groups containing from about 1 to about 3 carbon atoms;(6) long chain dialkyl sulfoxides containing one short chain alkyl orhydroxy alkyl radical of from 1 to about 3 carbon atoms (usually methyl)and one long hydrophobic chain which include alkyl, alkenyl, hydroxyalkyl, or keto alkyl radicals containing from about 8 to about 20 carbonatoms, from 0 to about 10 ethylene oxide moieties and from 0 to 1glyceryl moieties; (7) alkyl polysaccharide (APS) surfactants (e.g.alkyl polyglycosides), examples of which are described in U.S. Pat. No.4,565,647, which is incorporated herein by reference in its entirety,and which discloses APS surfactants having a hydrophobic group withabout 6 to about 30 carbon atoms and a polysaccharide (e.g.,polyglycoside) as the hydrophilic group; optionally, there can be apolyalkylene-oxide group joining the hydrophobic and hydrophilicmoieties; and the alkyl group (i.e., the hydrophobic moiety) can besaturated or unsaturated, branched or unbranched, and unsubstituted orsubstituted (e.g., with hydroxy or cyclic rings); and (8)polyoxyethylene alkyl ethers, having a general formula RO(CH₂CH₂)_(n)H),and polyethylene glycol (PEG) glyceryl fatty esters, having a generalformula R(O)OCH₂CH(OH)CH₂(OCH₂CH₂)_(n)OH), wherein n is from 1 to about200, preferably from about 20 to about 100, and R is an alkyl havingfrom about 8 to about 22 carbon atoms.

Certain nonionic surfactants can also function as foam stabilizers,viscosity control agents, or conditioning agents. Where included, thehair care composition may contain about 0.5 wt % to about 5.0 wt %nonionic surfactant, or about 0.75 wt % to about 2.0 wt %. Non limitingexamples of other anionic, amphoteric/zwitterionic, nonionic, oroptional additional surfactants suitable for use in the compositions aredescribed in McCutcheon's, Emulsifiers and Detergents, 1989 Annual,published by M. C. Publishing Co., and U.S. Pat. Nos. 3,929,678,2,658,072; 2,438,091; 2,528,378, which are incorporated herein byreference in their entirety.

2. Conditioning Agent

In one embodiment of the present invention, the hair care compositionscomprise one or more conditioning agents. Conditioning agents includematerials that are used to give a particular conditioning benefit tohair and/or skin. The conditioning agents useful in the hair carecompositions of the present invention typically comprise awater-insoluble, water-dispersible, non-volatile, liquid that formsemulsified, liquid particles. Suitable conditioning agents for use inthe hair care composition are those conditioning agents characterizedgenerally as silicones (e.g., silicone oils, cationic silicones,silicone gums, high refractive silicones, and silicone resins), organicconditioning oils (e.g., hydrocarbon oils, polyolefins, and fattyesters) or combinations thereof, or those conditioning agents whichotherwise form liquid, dispersed particles in the aqueous surfactantmatrix. In an embodiment, one or more conditioning agents are presentfrom about 0.01 wt % to about 10 wt %, from about 0.1 wt % to about 8 wt%, and from about 0.2 wt % to about 4 wt %, by weight of the entirecomposition.

3. Emulsifiers

A variety of anionic emulsifiers can be used in the shampoo compositionof the present invention as described below. The anionic emulsifiersinclude, by way of illustrating and not limitation, water-soluble saltsof alkyl sulfates, alkyl ether sulfates, alkyl isethionates alkylcarboxylates, alkyl sulfosuccinates, alkyl succinamates, alkyl sulfatesalts such as sodium dodecyl sulfate, alkyl sarcosinates, alkylderivatives of protein hydrolyzates, acyl aspartates, alkyl or alkylether or alkylaryl ether phosphate esters, sodium dodecyl sulphate,phospholipids or lecithin, or soaps, sodium, potassium or ammoniumstearate, oleate or palmitate, alkylarylsulfonic acid salts such assodium dodecylbenzenesulfonate, sodium dialkylsulfosuccinates, dioctylsulfosuccinate, sodium dilaurylsulfosuccinate, poly(styrene sulfonate)sodium salt, isobutylene-maleic anhydride copolymer, gum arabic, sodiumalginate, carboxymethylcellulose, cellulose sulfate and pectin,poly(styrene sulfonate), carrageenan, pectic acid, tragacanth gum,almond gum and agar; semi-synthetic polymers such as carboxymethylcellulose, sulfated cellulose, sulfated methylcellulose, carboxymethylstarch, phosphated starch, lignin sulfonic acid; and synthetic polymerssuch as maleic anhydride copolymers (including hydrolyzates thereof),polyacrylic acid, polymethacrylic acid, acrylic acid butyl acrylatecopolymer or crotonic acid homopolymers and copolymers,vinylbenzenesulfonic acid or 2-acrylamido-2-methylpropanesulfonic acidhomopolymers and copolymers, and partial amide or partial ester of suchpolymers and copolymers, carboxymodified polyvinyl alcohol, sulfonicacid-modified polyvinyl alcohol and phosphoric acid-modified polyvinylalcohol, phosphated or sulfated tristyrylphenol ethoxylates.

In addition, anionic emulsifiers that have acrylate functionality mayalso be used in the instant shampoo compositions. Anionic emulsifiersuseful herein include, but aren't limited to: poly(meth)acrylic acid;copolymers of (meth)acrylic acids and its (meth)acrylates with C1-22alkyl, C1-C8 alkyl, butyl; copolymers of (meth)acrylic acids and(meth)acrylamide; carboxyvinylpolymer; acrylate copolymers such asacrylate/C10-30 alkyl acrylate crosspolymer, acrylic acid/vinyl estercopolymer/acrylates/vinyl Isodecanoate crosspolymer,acrylates/palmeth-25 acrylate copolymer, acrylate/steareth-20 itaconatecopolymer, and acrylate/cetech-20 itaconate copolymer; polystyrenesulphonate, copolymers of methacrylic acid and acrylamidomethylpropanesulfonic acid, and copolymers of acrylic acid andacrylamidomethylpropane sulfonic acid; carboxymethycellulose; carboxyguar; copolymers of ethylene and maleic acid; and acrylate siliconepolymer. In an embodiment, the emulsifier, when present, ranges fromabout 0.01 wt % to about 5 wt %, by weight of the entire anti-dandruffhair care composition, or from about 0.1 wt % to about 4 wt %, or fromabout 0.1 wt % to about 3 wt %. Wt % is based on the weight of theentire composition.

4. Opacifiers

Some formulations are often opacified by incorporating materials thereinto achieve a cosmetically attractive pearl-like appearance, known aspearlescence. The opacifying or pearlescent materials include, but arenot limited to, titanium dioxide coated mica, iron oxide coated mica,ethylene glycol mono-stearate, ethylene glycol distearate, polyethyleneglycol distearate, bismuth oxychloride coated mica, myristyl myristate,guanine, glitter (polyester or metallic), and mixtures thereof. Otherpearlescent materials can be found in U.S. Pat. Nos. 4,654,207 and5,019,376, herein incorporated by reference. In an embodiment, theconcentration of the opacifier, when present, ranges from about 0.01 wt% to about 5 wt %, by weight of the entire anti-dandruff hair carecomposition, or from about 0.1 wt % to about 3 wt %, or from about 0.1wt % to about 2 wt %. Wt % is based on the weight of the entirecomposition.

5. Thickeners

Thickeners or rheology modifiers include, but are not limited to,acrylamide/ammonium acrylate copolymer (and) polyisobutene (and)polysorbate 20; acrylamide/sodium acryloyldimethyl tauratecopolymer/isohexadecane/polysorbate 80; acrylates copolymer;acrylates/beheneth-25 methacrylate copolymer; acrylates/C10-C30 alkylacrylate crosspolymer; acrylates/steareth-20 itaconate copolymer;ammonium polyacrylate/Isohexadecane/PEG-40 castor oil; C12-16 alkylPEG-2 hydroxypropylhydroxyethyl ethylcellulose (HM-EHEC); carbomer;crosslinked polyvinylpyrrolidone (PVP); dibenzylidene sorbitol;hydroxyethyl ethylcellulose (EHEC); hydroxypropyl methylcellulose(HPMC); hydroxypropylcellulose (HPC); methylcellulose (MC);methylhydroxyethyl cellulose (MEHEC); PEG-150/decyl alcohol/SMDIcopolymer; PEG-150/stearyl alcohol/SMDI copolymer; polyacrylamide/C13-14isoparaffin/laureth-7; polyacrylate 13/polyisobutene/polysorbate 20;polyacrylate crosspolymer-6; polyamide-3; polyquaternium-37 (and)hydrogenated polydecene (and) trideceth-6; polyurethane-39; sodiumacrylate/acryloyldimethyltaurate/dimethylacrylamide; crosspolymer (and)isohexadecane (and) polysorbate 60; sodium polyacrylate, andcombinations thereof. In an embodiment, the concentration of therheology modifier, when present, ranges from about 0.01 wt % to about 7wt %, by weight of the entire anti-dandruff hair care composition, orfrom about 0.1 wt % to about 5 wt %, or from about 0.2 wt % to about 4wt %. Wt % is based on the weight of the entire composition.

6. Buffers

The hair care compositions may have a pH ranging from about 3.0 to about10, which may be stabilized by the presence of a buffer system. Suitablebuffer solutions can be prepared using, for example, weak acid or weakbase systems using citric acid, phosphoric acid, phthalic acid, glycineor mixtures thereof. In each case the proper buffering capacity isobtained by adjusting the final pH of the compositions to within the pHrange indicated above. This may be done by using an acid (e.g., HCl,citric acid) or a base (e.g., NaOH, sodium citrate) as may be needed.The amount of buffer employed in the present compositions depends on theparticular acid chosen but is generally from about 0.1 wt % to about 10wt %, preferably from about 0.2 wt % to about 5 wt %. Wt % is based onthe weight of the entire composition.

Additional agents, such as benefit agents, may also be included in thehair care compositions. The benefit agent may comprise a materialselected from the group consisting of perfumes; brighteners; enzymes;sensates (cooling or warming); attractants, antibacterial agents; dyes;pigments; bleaches; and mixtures thereof. It should be furtherappreciated that the inventive combination of natural anti-dandruffactives disclosed herein may also be used in combination with secondaryscalp benefit agents, such as soluble and/or insoluble anti-dandruffactives. Such anti-dandruff actives include but are not limited toazoles, such as ketoconazole, econazole, climbazole, and elubiol;keratolytic agents such as salicylic acid; and zinc-containing layered(ZLM) materials, pyridinethione anti-dandruff particulates such as zincpyrithione, coal tar, sulfur, charcoal, whitfield's ointment,castellani's paint, aluminum chloride, gentian violet, octopirox(piroctone olamine), ciclopirox olamine, undecylenic acid and it's metalsalts, potassium permanganate, selenium sulphide, sodium thiosulfate,propylene glycol, urea preparations, griseofulvin, 8-Hydroxyquinolineciloquinol, thiobendazole, thiocarbamates, haloprogin, polyenes,hydroxypyridone, morpholine, benzylamine, allylamines (such asterbinafine), Sensiva SC-50, Elestab HP-100, azelaic acid, lyticase,iodopropynyl butylcarbamate (IPBC), isothiazalinones such as octylisothiazalinone, other natural oils, extracts, or compounds such as oilof bitter orange, tea tree oil, clove leaf oil, coriander, palmarosa,berberine, thyme red, cinnamon oil, cinnamic aldehyde, citronellic acid,hinokitol, ichthyol pale, and combinations thereof. In an embodiment,the concentration of the secondary scalp benefit agent ranges from about0.01 wt % to about 5 wt %, by weight of the entire anti-dandruff haircare composition, or from about 0.1 wt % to about 3 wt %, or from about0.1 wt % to about 2 wt %. Wt % is based on the weight of the entirecomposition. Alternatively, the inventive combination of naturalanti-dandruff actives disclosed herein may also be void of any of theforegoing recited soluble and/or insoluble anti-dandruff actives.

The anti-dandruff hair care compositions are generally prepared byconventional methods known in the art shampoo compositions. Such methodstypically involve mixing of the ingredients in one or more steps to arelatively uniform state, with or without heating, cooling, applicationof vacuum, and the like. The compositions are prepared such as tooptimize stability (physical stability, chemical stability,photostability) and/or delivery of the active materials. Thisoptimization may include appropriate pH, and exclusion of materials thatcan complex or react with the active agent(s) and thus negatively impactstability or delivery.

The anti-dandruff hair composition may be in a single phase or a singleproduct, or the anti-dandruff hair composition may be in a separatephases or separate products. If two products are used, the products maybe used together, at the same time or sequentially. Sequential use mayoccur in a short time period, such as immediately after the use of oneproduct, or it may occur over a period of hours or days.

Use of the Anti-dandruff Composition: According to yet anotherembodiment of the present invention, a method is provided for thetreatment of a subject having dandruff and/or to prevent or inhibit theonset of dandruff symptoms associated with the proliferation of yeastsof the Malassezia genus on a scalp of a subject. The method includescontacting the subject's scalp or keratinous tissue with an effectivequantity of the anti-dandruff composition of the present invention. Theanti-dandruff composition may be massaged onto the scalp and shouldremain in contact with the subjects scalp or keratinous tissue for aduration of at least 15 seconds or more. Depending on the formulation,the anti-dandruff composition may be a leave in or it may be rinsed out.

Accordingly, in another embodiment, the method comprises topicallyapplying an anti-dandruff composition comprising an effective amount ofthe anti-dandruff actives to a region of the subject's skin whereinhibition of Malassezia furfur is needed or wanted, where theanti-dandruff actives remain in contact with the region for a durationof 15 seconds or more; and then rinsed out. In still another embodiment,the method comprises applying the composition according to a regimen,wherein said regimen comprises: (a) cleansing the scalp to form acleansed scalp; (b) topically applying the anti-dandruff composition tosaid cleansed scalp.

The anti-dandruff composition may be used daily, weekly, or in a varietyof regimens. The anti-dandruff composition may be used more than once aday, such as at night and in the morning. The product may be used afterwashing the hair (also on wet or dry hair), which may mean using thecomposition more than once per day on certain days or use only a fewtimes per week. The anti-dandruff composition may be used three timesper day, twice per day, once per day, six times per week, five times perweek, four times per week, three times per week, two times per week, orone time per week. In some embodiments, the anti-dandruff composition isused four, five, six or seven times per week.

According to another embodiment, the anti-dandruff composition isapplied to at least once a day for at least about four weeks, or atleast twice a day for at least about four weeks. According to anotherembodiment, the anti-dandruff composition is applied at least once a dayfor at least about eight weeks. The anti-dandruff composition may beused by males and females.

Formulations and Examples

The following are non-limiting examples of the present invention. Theexamples are given solely for the purpose of illustration and are not tobe construed as limitations of the present invention, as many variationsthereof are possible without departing from the spirit and scope of theinvention, which would be recognized by one of ordinary skill in theart. In the examples, all concentrations are listed as weight percent,unless otherwise specified and may exclude minor materials such asdiluents, filler, and so forth. The listed formulations, therefore,comprise the listed components and any minor materials associated withsuch components. As is apparent to one of ordinary skill in the art, theselection of these minors will vary depending on the physical andchemical characteristics of the particular ingredients selected to makethe present invention as described herein.

Anti-Dandruff Actives

Extract of Punica granatum: 25 g of the flaked Punica granatum rind rawmaterial (obtained from Pradip Agrotech Pvt Ltd.; Solapur, Maharashtra,India; phenolic content of 24.2 GAE/g) was extracted with 50% aqueousethanol at 65° C. for 30 min and filtered to remove the undissolvedsolids from the filtrate. The undissolved solids were further extractedfive more times with the same procedure as described above. The combinedfiltrates were filtered through a 10-13 micron filter cloth, evaporatedin a rotary evaporator under vacuum to yield 13.98 g of dried solidshaving a phenolic content of 43.5 GAE/g (mass yield=55.92%). Based onLC/MS-QTOF analysis, this extract of Punica granatum contains gallicacid, punicalagin α, punicalagin β, punicalin, ellagic acid hexoside,ellagic acid pentoside, ellagic acid deoxyhexoside, ellagic acid, andgalloyl HHDP hexoside. HPLC quantification against standards provided3.9 wt % ellagic acid, 0.5 wt % gallic acid, 0.22 wt % punicalagin B,and 0.05 wt % punicalagin A. This unstandardized product (PE 1) can bediluted with a sufficient quantity of glycerol, and then filteredthrough a 400 micron metal sieve, to form a standardized solution having12% GAE (PE 2). Alternatively, subjecting fresh Punica granatum rind rawmaterial to aqueous pressing and purification by column chromatography(DIAION™ HP20 resin, wash with water and elute with 50% aqueousethanol), and spray drying yielded an unstandardized product with about75 GAE and 30 wt % punicalagins, which was also dissolved in glycerol toform a standardized solution having 12% GAE (PE 3).

Essential oil of Trachyspermum ammi: The essential oil (EO) of Ajowan isproduced by the steam distillation of ground, dried seeds ofTrachyspermum ammi (obtained from Shree Agro International; Unja,Gujarat, India). The ground seeds are charged to the vessel andmoistened before applying steam. Direct steam is applied, and thedistillation continued for a minimum of about 15 hours to obtain a totalyield of Ajowan EO in about 2 wt % to about 2.5 wt %, based on the driedweight of the Ajowan seeds (AJ 1). The EO product is a liquid and haspale yellow to brownish yellow color. It has the characteristic odor ofcyminic, with a thymolic after note. Analysis by GC-MS using an Agilent5977A, equipped with GC-7890B and 7693 auto sampler, operated inelectron impact (EI) mode (70 ev) revealed that the major components ofAjowan EO are gamma-terpinene (45.7%), p-cymene (22.0%), and thymol(23.2%), where % is FID area % from the GC-MS analysis. Ajowan EO may beobtained from Kancor Ingredients LTD (Kerala, India).

Essential oil of Mentha arvensis: The essential oil (EO) of corn mint isproduced by the steam distillation of the flowering herb of Menthaarvensis. The semi-dried corn mint leaves (obtained from Bareilly, UttarPradesh, India) are charged to a steam distillation vessel. Steam isslowly applied to distill out the EO and the process continued whilemonitoring the EO production. Average distillation time is approximately5 to 7 hours, with a total yield of approximately 1.4 wt % to 1.6 wt %,based on the weight of the semi-dried corn mint leaves (CM 1). The cornmint EO product is a colorless or pale yellow liquid. Analysis by GC-MSrevealed that the major constituent of corn mint essential oil isL-menthol (76.1%) and the other notable constituents include menthone(6.8%), isomenthone (3.6%), neomenthol (2.1%), menthyl acetate (2.1%),and limonene (1.7%), where % is FID area % from the GC-MS analysis. Thecorn mint EO may be obtained from Kancor Ingredients LTD (Kerala,India).

Combinations: Based on their additive and synergistic anti-dandruffactivities (discussed below), blends or mixtures of the ingredients,along with optional carrier(s) and other functional ingredients may beadvantageously prepackaged and/or blended with a variety of hair careingredients.

TABLE 1 ANTI-DANDRUFF SHAMPOO FORMULATIONS Control Ex. 1 Ex. 2 Ex. 3 Ex.Ingredient Tradename A B C D E Distilled water n/a 64.23 62.73 63.1361.70 61.9 ACRYLATES/C10-30 ALKYL CARBOPOL ® 0.20 0.2 0.2 0.19 0.19ACRYLATE CROSSPOLYMER ETD 2020 SODIUM HYDROXIDE 20% IN n/a 0.10 0.1 0.10.09 0.09 WATER SODIUM LAURETH SULFATE TEXAPON ® 21.00 21.00 21.0 19.8119.8 AND WATER N70 COCAMIDE MIPA COMPERLAN ® IP 0.1 0.1 0.1 0.09 0.09GLYCOL DISTEARATE TEGIN ® BL 315 2.00 2.00 2.00 1.89 1.89 DISODIUMMIRANOL ® 8.00 8.00 8.00 7.55 7.58 COCOAMPHODIACETATE C2M CONC 2.50 2.502.50 2.36 2.37 DIMETHICONE XIAMETER ® PMX-200 SILICONE FLUID 60000 CSTHYDROXYPROPYL GUAR & JAGUAR ® 0 0 0 0.28 0.28 HYDROXYPROPYL GUAR - C162HYDROXYPROPYLTRIMONIUM CHLORIDE GUAR - JAGUAR ® 0.3 0.3 0.3 0 0HYDROXYPROPYLTRIMONIUM C13S CHLORIDE PPG-5-CETETH-20 PROCETYL ™ 0.3 0.30.3 0.28 0.28 AWS PE 2 0 1.67 1.67 1.67 1.67 CM 1 0 1.0 0.5 1 0.5 AJ 1 00 0.1 0 0.1 CITRIC ACID 20% IN WATER N/A 0.10 0.1 0.1 0.09 0.09 PEG-32PLURACARE ® 0 0 0 3 3 E 1500 Glycerine n/a 1.17 0 0 0 0 100 100 100 100100 PE - pomegranate extract; AJ - ajowan essential oil; CM - corn mintessential oil; Part A - Shampoo chassis; Part B - anti-dandruff actives;Part C - pH or viscosity modifiers.

Preparation of the anti-dandruff shampoo begins with dispersing theCARBOPOL® in 40% of water and then neutralizing to pH=6 with sodiumhydroxide. JAGUAR® C162 is dispersed in the remaining water and thenadded to the CARBOPOL® solution. After the addition of TEXAPON® N70, themixture is heated to 70° C., the solid raw materials are added, i.e.,COMPERLAN®, TEGIN® BL315. When the solids were well dissolved, themixture was allowed to cool down, and the other ingredients (includingthe anti-dandruff actives PE 2, CM 1, and AJ 1) added and mixed welluntil complete homogeneity. pH was adjusted to 5.65 with citric acid andviscosity adjusted with PLURACARE® E1500.

Antimicrobial Activity and Interaction Testing

Briefly, as is commonly known by those skilled in the art of the instantdisclosure, assessment of Malassezia furfur inhibition may beaccomplished following standard and accepted practices, such as thatdescribed in U.S. Patent Application Publication No. 2008/0249186.Accordingly, an external testing laboratory performed a series ofagainst Malassezia furfur to evaluate antimicrobial activity andinteractions (see Lens, et al. “Methods for the evaluation ofantimicrobial activity of essential oils,” J. Pharm. Belg. 1987).Inhibitory activity testing was conducted by mixing 100 μl of variousdilutions of the test product at a double concentration with an equalvolume (100 μl) of a double strength Difco™ Sabouraud dextrose brothsupplemented with olive oil, inoculated between 2 to 6×10⁵ cfu/mL. Afterincubation (24-72 hours, at 32.5° C.±2.5° C.), a spectrophotometricreading at 620 nm is performed and the percentage of growth calculatedfrom optical density (OD) measuring each concentration with respect to apositive growth control according to the following equation:% ofgrowth=[OD_(product)−OD_(absorbance-control))]/(OD_(positive growth-control)).

Each concentration was tested in triplicate, and two assays wereperformed per product. The positive growth control consisted of 100 μl1% agar solution mixed with 100 μl of inoculated broth.

TABLE 2 Minimum Inhibitory Concentrations against M. furfur. SampleComment Test 1 Test 2 M. furfur strain PE 1 MICRA 150624  0.1%  0.1% CIP1634.84 PE 2 MICRA-L 170105  0.1%  0.1% CIP 1634.84 PE 3 MICRA-P 0.05%0.05% CBS 1878 CM 1 OMAO 2006501  0.5%  0.5% CIP 1634.84 CM 1 OMAO2006501    1%    1% CBS 1878 AJ 1 AJTEO 204829    1%    1% CIP 1634.84AJ 1 AJTEO 204829  0.5%  0.5% CBS 1878 PU Punicalagins A&B 0.05% 0.05%CBS 1878 EA Ellagic Acid  0.5%  0.5% CBS 1878 Shampoo A Control, Table 1  10% — CIP 1634.84 Shampoo B Example 1, Table 1   ≤5%   ≤1% CIP 1634.84Shampoo C Example 2, Table 1   ≤5%   ≤1% CIP 1634.84 Shampoo FComparative   ≤5% — CIP 1634.84 PE-pomegranate extract; AJ-ajowanessential oil; CM-corn mint essential oil; PU-punicalagins A&B;EA-ellagic acid; Comparative Shampoo F = HEAD & SHOULDERS ®, Procter &Gamble, UK.; Classic, Lot. No. (L) 60435395KF.

Inhibition studies revealed that the shampoo formulations including aplurality of the nature-derived anti-dandruff actives of the presentinvention (i.e., Shampoos B and C) possessed enhance activity over thecontrol (Shampoo A), and were approximately as effective as thecomparative Shampoo F, which utilizes synthetic zinc pyrithione.

Study of Associations. After obtaining the MIC levels for each of theanti-dandruff actives by broth dilution method, a checkerboard titrationtechnique was performed to assess the synergistic activity of thecombinations. In order to evaluate the activity of the combinations ofthe anti-dandruff actives, a Fractional Inhibitory Concentration index(FIC_(index)) was calculated: (FIC_(index))=FIC^(A)+FIC^(B), whereFIC^(A) and FIC^(B) represent the minimum concentrations inhibiting theM. furfur growth for anti-dandruff actives A and B, respectively. AndFIC^(A)=MIC^(A) _(combination)/MIC^(A) _(alone), and FIC^(B)=MIC^(B)_(combination)/MIC^(B) _(alone).] A mean FIC index was calculated basedon the following equation: FIC_(index)=FIC^(A)+FIC^(B). Synergism isdefined as FIC≤0.75; additive as FIC˜1; indifference as 1<FIC≤2; andantagonism is defined as FIC>2, as reported by J. L. Pons; N.Bonnaveiro; J. Chevalier; and A. Crémieux, “Evaluation of antimicrobialinteractions between chlorhexidine, quaternary ammonium compounds,preservatives and excipients,” J. Appl. Bacteriology, 1992, 73(5),395-400.

TABLE 3 Association testing of anti-dandruff active combinations. MIC inthe Samples MIC A MIC B associations FIC A B M. furfur strain Alone %Alone % A % B % Index Conclusion PE 2 AJ 1 CIP 1634.84 0.2 1 0.025 0.50.63 Synergistic PE 1 CM 1 CIP 1634.84 0.2 0.5 0.1 0.25 1.00 Additive CM1 AJ 1 CIP 1634.84 0.5 1 0.0625 0.5 0.63 Synergistic AJ 1 PU CBS 18780.25 0.05 0.0625 0.0125 0.5 Synergistic AJ 1 EA CBS 1878 0.25 0.5 0.250.25 1.5 Indifferent PE 3 AJ 1 CBS 1878 0.05 0.25 0.0125 0.125 0.75Synergistic PE 3 CM 1 CBS 1878 0.05 1 0.0125 0.25 0.5 Synergistic PE 3TML CBS 1878 0.05 0.05 0.0125 0.05 1.25 Indifferent PE 3 GTP CBS 18780.05 >1 0.05 0.125 1.13 Indifferent PE 3 PCY CBS 1878 0.1 0.5 0.01250.25 0.625 Synergistic PE - pomegranate extract; AJ - ajowan essentialoil; CM - corn mint essential oil; TML - thymol; GTP - gamma-terpinene;PCY - para-cymene

The association testing of the nature-derived anti-dandruff actives ofthe present invention utilizing the checkerboard titration techniquerevealed the synergistic activity of the combinations of a) thepunicalagin composition (PE 2) and the first monoterpenoid composition(AJ 1); b) the second monoterpenoid composition (CM1) and the firstmonoterpenoid composition (AJ 1); and the first monoterpenoidcomposition (AJ 1) and punicalagins A & B (PU). The combination of thepunicalagin composition (PE 1) and the second monoterpenoid composition(CM 1) was shown to be additive, whereas the combination of the firstmonoterpenoid composition (AJ 1) and ellagic acid (EA) was shown to beindifferent.

The association testing of the major components of first monoterpenoidcomposition (i.e., thymol (TML), gamma-terpinene (GTP), and para-cymene(PCY)) and the pomegranate extract having a punicalagins content ofabout 30 wt % on a dry weight basis (PE 3) revealed that thebi-component mixture of PE 3 and para-cymene (PCY) demonstratedsynergistic activities against Malassezia furfur. The bi-componentmixture of the punicalagin composition having a punicalagins content ofat least 30 wt % on a dry weight basis (PE 3) and the secondmonoterpenoid composition (CM 1) was shown to be synergistic againstMalassezia furfur.

Clinical Study

Protocol: Over 80 prescreened subjects having dandruff symptomsparticipated in a 28 day blind study, prior to which subjects completeda 14-day wash-out period consisting of a daily wash using a neutralshampoo (Szampon Familijny®, Pollena-Savona Sp. z o. o.; Batches 170270,160492). In the study, inventive Shampoo D (Table 1, Example 3;combination of pomegranate extract and corn mint EO) and inventiveShampoo E (Table 1, Example 4; combination of pomegranate extract, cornmint EO, and ajowan EO) were tested against comparative Shampoo F (HEAD& SHOULDERS®, Procter & Gamble, UK.; Classic, Lot. No. (L) 60435395KF,zinc pyrithione active). Prior to and after adhering to the required 28day protocol, each scalp of each subject was assessed for adherent andnon-adherent dandruff and given a score based on the qualitativedandruff criteria provided in Table 4.

TABLE 4 The clinical “total dandruff score” is the sum of the adherentand non-adherent dandruff. Qualitative Dandruff Scoring. ScoreNon-adherent dandruff Adherent dandruff 0 No dandruff No squamae 1 A fewdispersed A few dispersed dandruff flakes squamae flakes 2 A smallquantity A small quantity of of dandruff flakes squamae dandruff 3 Amoderate quantity A moderate quantity of dandruff flakes of squamaedandruff 4 A large quantity A large quantity of dandruff of dandruff 5 Avery large quantity A very large quantity of dandruff flakes of squamaeover the whole scalp

TABLE 5 Total Dandruff Scoring Results. Non-adherent Adherent Samplescore score Total Shampoo D −1.23 −0.86 −2.09 Shampoo E −1.01 −0.87−1.87 Shampoo F −1.77 −1.37 −3.13

After following the prescribed 28 day testing protocol, all the testproducts (Shampoos D-F) were very well tolerated on the cutaneous level,and demonstrated significant decrease in adherent, non-adherent, andtotal dandruff score (see Table 5). The inventive shampoos (Shampoo Dand E), which utilize nature-based, naturally-derived anti-dandruffactives, were shown to be effective at treating dandruff without usingthe synthetic zinc pyrithione anti-dandruff active (which is used incomparative Shampoo F).

Although not wishing to be limited by any particular theory, it isbelieved that topical application of the anti-dandruff actives in adermatologically-acceptable carrier decreases the physical signs ofdandruff by inhibiting the proliferation of Malassezia furfur.Accordingly, topical application of the anti-dandruff compositions maybe used to treat dandruff or used prophylactically to inhibit the onsetof dandruff caused by the proliferation of Malassezia furfur.

All documents cited in the Detailed Description of Embodiments of theInvention are, in relevant part, incorporated herein by reference; thecitation of any document is not to be construed as an admission that itis prior art with respect to the present invention. To the extent thatany meaning or definition of a term in this document conflicts with anymeaning or definition of the same term in a document incorporated byreference, the meaning or definition assigned to that term in thisdocument shall govern. The dimensions and values disclosed herein arenot to be understood as being strictly limited to the exact numericalvalues recited. Instead, unless otherwise specified, each such dimensionis intended to mean both the recited value and a functionally equivalentrange surrounding that value. For example, a dimension disclosed as “25°C.” is intended to mean “about 25° C.”

While the present invention is illustrated by the description of one ormore embodiments thereof, and while embodiments have been described inconsiderable detail, they are not intended to restrict or in any waylimit the scope of the appended claims to such detail. Additionaladvantages and modification will readily appear to those skilled in theart. The invention in its broader aspects is therefore not limited tothe specific details, representative product and method, andillustrative examples shown and described. Accordingly, departures fromsuch details may be made without departing from the scope of the generalinventive concept embraced by the following claims.

The invention claimed is:
 1. An anti-dandruff composition comprising: acombination of anti-dandruff actives, said anti-dandruff activescomprising: a punicalagin composition, a first monoterpenoid compositioncomprising p-cymene, a second monoterpenoid composition comprisingmenthol; and a dermatologically-acceptable carrier; wherein thecombination of anti-dandruff actives is present in the anti-dandruffcomposition in an amount effective to inhibit a proliferation ofMalassezia furfur and thereby treat dandruff; and wherein the firstmonoterpenoid composition further comprises thymol and gamma-terpinene.2. The anti-dandruff composition of claim 1, wherein the secondmonoterpenoid composition further comprises menthone, isomenthone,menthyl acetate, neomenthol, limonene, or combinations thereof.
 3. Theanti-dandruff composition of claim 1, wherein the punicalagincomposition is derived from extracting pomegranate rind with an aqueousextraction liquid comprising water or an aqueous alcoholic solution. 4.The anti-dandruff composition of claim 1, wherein the punicalagincomposition comprises a polyphenol content of at least 30 gallic acidequivalents (GAE), on a dry weight basis.
 5. The anti-dandruffcomposition of claim 1, wherein the punicalagin composition comprisespunicalagin A, punicalagin B, or both in 0.1 wt % or more, based on adry weight basis.
 6. The anti-dandruff composition of claim 1, whereinthe punicalagin composition comprises less than 5 wt % ellagic acid,based on a dry weight basis.
 7. The anti-dandruff composition of claim1, wherein the first monoterpenoid composition is obtained from anajowan essential oil.
 8. The anti-dandruff composition of claim 1,wherein the second monoterpenoid composition is obtained from a cornmint essential oil.
 9. The anti-dandruff composition of claim 1, whereinthe first monoterpenoid composition is present in an amount in a rangefrom 0.1 wt % to 5 wt % based on the entire weight of the composition.10. The anti-dandruff composition of claim 1, wherein the punicalagincomposition is present in an amount in a range from 0.1 wt % to 10 wt %based on the total weight of the anti-dandruff composition.
 11. Theanti-dandruff composition of claim 1, wherein the second monoterpenoidcomposition is present in an amount in a range from 0.25 wt % to 10 wt %based on the total weight of the anti-dandruff composition.
 12. Theanti-dandruff composition of claim 1, wherein the punicalagincomposition is present in an amount in a range from 0.1 wt % to 10 wt %;wherein the first monoterpenoid composition is present in an amount in arange from 0.1 wt % to 5 wt %; wherein the second monoterpenoidcomposition is present in an amount in a range from 0.25 wt % to 10 wt%; wherein the dermatologically-acceptable carrier comprises water and adetersive surfactant; and wherein the wt % is based on the total weightof the anti-dandruff composition.
 13. The anti-dandruff composition ofclaim 12, wherein the dermatologically-acceptable carrier comprisingwater and the detersive surfactant is present in a range from about 30wt % to about 99 wt %, based on the total weight of the anti-dandruffcomposition.
 14. A method of treating a subject having dandruff dandruffsymptoms associated with a proliferation of Malassezia furfur on a scalpof the subject, comprising: contacting the subject's scalp or keratinoustissue with an effective quantity of the anti-dandruff composition ofclaim
 1. 15. The method of claim 14, further comprising massaging ontothe scalp the anti-dandruff composition; and maintaining theanti-dandruff composition in contact with the subject's scalp orkeratinous tissue for a duration of at least 15 seconds or more.
 16. Themethod of claim 15, further comprising rinsing out the anti-dandruffcomposition.
 17. The method of claim 14, wherein the punicalagincomposition is present in the anti-dandruff composition an amount in arange from 0.1 wt % to 10 wt %; wherein the first monoterpenoidcomposition is present in an amount in a range from 0.1 wt % to 5 wt %;wherein the second monoterpenoid composition is present in an amount ina range from 0.25 wt % to 10 wt %; wherein thedermatologically-acceptable carrier comprises water and a detersivesurfactant; and wherein the wt % is based on the total weight of theanti-dandruff composition.
 18. The method of claim 17, wherein thepunicalagin composition is derived from extracting pomegranate rind withan aqueous extraction liquid comprising water or an aqueous alcoholicsolution; wherein the second monoterpenoid composition further comprisesmenthone, isomenthone, menthyl acetate, neomenthol, limonene, orcombinations thereof.
 19. The method of claim 14, wherein, based on adry weight basis, the punicalagin composition comprises punicalagin A,punicalagin B, or both in 0.1 wt % or more; and wherein the punicalagincomposition comprises less than 5 wt % ellagic acid.
 20. Theanti-dandruff composition of claim 1, wherein the p-cymene is present inthe first monoterpenoid composition in an amount of at least 20 wt %,based on the weight of the first monoterpenoid composition.
 21. Theanti-dandruff composition of claim 1, wherein the first monoterpenoidcomposition comprises 20-60 wt % gamma-terpinene, 20-60 wt % p-cymene,and 20-60 wt % thymol, based on the weight of the first monoterpenoidcomposition.
 22. The anti-dandruff composition of claim 1, wherein acombined mass of the gamma-terpinene, p-cymene, and thymol constitute atleast 80 wt % of the first monoterpenoid composition.
 23. Ananti-dandruff composition comprising: a combination of anti-dandruffactives, said anti-dandruff actives comprising: a punicalagincomposition, a first monoterpenoid composition comprising p-cymene, asecond monoterpenoid composition comprising menthol; and adermatologically-acceptable carrier; wherein the combination ofanti-dandruff actives is present in the anti-dandruff composition in anamount effective to inhibit a proliferation of Malassezia furfur andthereby treat dandruff; wherein the first monoterpenoid compositionfurther comprises thymol and gamma-terpinene; and wherein the secondmonoterpenoid composition further comprises menthone, isomenthone,menthyl acetate, neomenthol, limonene, or combinations thereof.